D-Homopregnanes

ABSTRACT

D-Homopregnanes of the formula ##STR1## wherein X is hydrogen, Y is hydroxy or X and Y taken together denote an oxygen to carbon bond; R 6  is hydrogen, R 7  is hydrogen, lower alkanoylthio or aroylthio, or R 6  and R 7  taken together denote a carbon to carbon bond and the dotted line in the 1,2-position of the A-ring together with the corresponding solid line denotes a single or double carbon to carbon bond or a pharmaceutically acceptable basic addition salt thereof when Y is hydroxy having diuretic activity are disclosed.

This is a division, of application Ser. No. 921,036 filed June 30, 1978,now U.S. Pat. No. 4,202,823.

DESCRIPTION OF THE INVENTION

The present invention relates to D-homosteroids. More particularly, theinvention is concerned with D-homopregnanes, a process for thepreparation thereof and pharmaceutical compositions containing same.

The D-homosteroids provided by the present invention are compounds ofthe general formula ##STR2## wherein X is hydrogen, Y is hydroxy or Xand Y taken together denote an oxygen to carbon bond; R⁶ is hydrogen, R⁷is hydrogen, lower alkanoylthio or aroylthio, or R⁶ and R⁷ takentogether denote a carbon to carbon bond and the dotted line in the1,2-position of the A-ring together with the corresponding solid linedenotes a single or double carbon to carbon bond or a pharmaceuticallyacceptable basic addition salt thereof when Y is hydroxy.

As used throughout the specification and appended claims, the term"alkanoylthio" denotes the residue obtained by removal of the thiolproton of the thiolcarboxylic acid group (COSH) of straight- orbranched-chain, saturated or unsaturated aliphatic thiolcarboxylicacids. Examples of the aforementioned alkanoylthio groups which containpreferably from 1 to 15 carbon atoms are formylthio, acetylthio,propionylthio, butyrylthio, pentanoylthio, hexanoylthio,undecylenoylthio, oleoylthio, cyclohexylpropionylthio,cyclopentylpropionylthio and phenacetylthio. The term "aroylthio"denotes the residue obtained by removal of the thiol proton of thethiolcarboxylic acid group (COSH) of aromatic thiolcarboxylic acids. Anexample of the aforementioned aroylthio group is benzoylthio. The term"lower" denotes a group having a carbon skeleton containing 1 to 7carbon atoms.

In the formulas presented herein, the various substituents are joined tothe cyclic nucleus by one of three notations: a solid line ( ),indicating a substituent which is in the β-orientation (above the planeof the paper), a dotted line ( ), indicating a substituent which is inthe α-orientation (below the plane of the paper), or a wavy line ( ),indicating a substituent which may either be in the α- or β-orientation.The position of the methyl groups in the 10- and 13-positions have beenarbitrarily indicated as the δ-orientation which is consistent with theabsolute stereochemistry of the products described in the examples. Itis to be understood, however, that in the formulas presented both in thespecification and in the appended claims, there is intended to berepresented both of the enantiomeric series, as well as mixturesthereof, such as racemic mixtures.

As pharmaceutically acceptable basic addition salts of the acids offormula I, i.e., the homopregnanes of formula I wherein Y is hydrogen,there may be mentioned, in particular, alkali metal salts, e.g., sodiumand potassium salts, ammonium salts and alkaline earth metal salts,e.g., calcium salts. The potassium salts are preferred.

The methyl group in the 6-position of the steroid nucleus may occupy theα- or β-configuration, the 6α-methyl configuration being preferred.

Preferred D-homopregnanes of formula I are those in which R⁷ is loweralkanoylthio or arolythio. Particularly preferred are those in which R⁷is lower alkanoylthio. Furthermore, the lactones of formula I, i.e., thecompounds of formula I wherein X and Y taken together denote an oxygento carbon bond, are preferred.

According to the process provided by the present invention, theD-homopregnanes, i.e., the compounds of formula I and theirpharmaceutically acceptable basic addition salts are prepared by

(a) hydrogenating or isomerizing a D-homopregnane of the formula##STR3## wherein X, Y and R⁷ are as above, or a salt thereof, or (b)reacting a D-homopregnane of the formula ##STR4## wherein X and Y are asabove, or a salt thereof with a compound of the formula

    R.sup.7 H

wherein R⁷ is as above, or

(c) dehydrogenating a D-homopregnane of the formula ##STR5## wherein X,Y, R⁶ and R⁷ are as above, or a salt thereof in the 1,2-position and/orin the 6,7-position when R⁶ and R⁷ are each hydrogen, or

(d) cleaving the lactone ring of a D-homopregnane of the formula##STR6## wherein the dotted lines in the 1,2-position of the A-ring andthe 6,7-position of the B-ring each taken together with thecorresponding solid lines denote a single or double carbon to carbonbond, or

(e) lactonizing a D-homopregnane of the formula ##STR7## wherein thedotted lines in the 1,2-position of the A-ring and the 6,7-position ofthe B-ring each taken together with the corresponding solid lines denotea single or double carbon to carbon bond, or a salt thereof, or

(f) oxidizing a D-homopregnane of the formula ##STR8## wherein X and Yare as above, or a salt thereof to give corresponding Δ⁴ -, Δ⁴,6 - orΔ¹,4,6 -3-ketones.

The hydrogenation of the 6-methylene group of the D-homopregnane offormula II according to embodiment (a) of the present process can becarried out by known methods using hydrogenation catalysts, e.g., noblemetal catalysts, such as palladium.

The isomerization of the 6-methylene group of the D-homopregnane offormula II to a 6-methyl-Δ⁶ -function can also be carried out by knownmethods, e.g., catalytically. Suitable isomerization catalysts are,e.g., metal hydrogenation catalysts, preferably palladium in ethanol.Expeditiously, a hydrogen donor, such as cyclohexane, is added toactivate the catalyst. Undesired side-reactions, such as hydrogenationsby means of the hydrogen donor can be avoided by buffering the mixture.

According to embodiment (a) of the present process, there are obtainedD-homopregnanes of formula I in which R⁶ and R⁷ are each hydrogen or R⁶and R⁷ taken together denote a carbon to carbon bond and the dotted linein the 1,2-position of the A-ring taken together with the correspondingsolid line denotes a single carbon to carbon bond.

The introduction of the lower alkanoylthio or aroylthio group R⁷ intothe D-homopregnanes of formula III according to embodiment (b) of thepresent process can be carried out by known methods by reacting aD-homopregnane of formula III with a suitable thiocarboxylic acid. Thereaction can be carried out in an inert solvent, such as an ether, e.g.,dioxan or tetrahydrofuran, an alcohol, e.g., methanol or ethanol or achlorinated hydrocarbon, e.g., chloroform. Alternatively, thethiocarboxylic acid may be used in excess to serve also as the solvent.

According to embodiment (b) of the present process there are obtainedD-homopregnanes of formula I in which R⁶ is hydrogen, R⁷ is alkanoylthioor aroylthio and the dotted line in the 1,2-position of the A-ring takentogether with the corresponding solid line denotes a single carbon tocarbon bond.

The 1,2-dehydrogenation of the D-homopregnanes of formula IV accordingto embodiment (c) of the present process can be carried out by knownmethods. For example, microbiologically or by means of dehydrogenationagents, such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone,chloranil, thallium triacetate or lead tetraacetate. Suitablemicroorganisms for the 1,2-dihydrogenation are, e.g., Schizomycetes,particularly those of the genera Arthrobacter, e.g., A. simplex ATCC6946, Bacillus, e.g., B. lentus ATCC 13805 and B. sphaericus ATCC 7055,Pseudomonas, e.g., P. aeruginosa IFO 3505, Flavobacterium, e.g., F.flavescens IFO 3058, Lactobacillus, e.g., L. brevis IFO 3345 andNocardia, e.g., N. opaca ATCC 4276.

The introduction of the Δ⁶ -double bond can be performed, e.g., by usinga substituted benzoquinone such as chloranil or2,3-dichloro-5,6-dicyanobenzoquinone (see J. Am. Chem. Soc., 82, 4293(1960); 81, 5951 (1959)) or by using manganese dioxide (see J. Am. Chem.Soc., 75, 5932 (1953)).

The 1,4,6-trisdehydro-D-homopregnanes of formula I can also be obtaineddirectly by using 2,3-dichloro-5,6-dicyanobenzoquinone or chloranil.

Embodiment (c) of the present process yields 4,6-dienes, 1,4-dienes and1,4,6-trienes of formula I.

The cleavage of the lactone ring present in the D-homopregnanes offormula V according to embodiment (d) of the present process can becarried out by known methods. For example, by using a base such aspotassium hydroxide or sodium hydroxide in a solvent, e.g., an alcohol,such as methanol, ethanol or isopropanol, at a temperature between about0° C. and the reflux temperature of the mixture, preferably at about 50°C. The salts so obtained, which correspond to the employed base, can beconverted into the free acids of formula I by acidification, e.g., byusing hydrochloric acid. The latter can be converted into salts bytreatment with suitable bases.

Embodiment (d) of the present process yields D-homopregnanes of formulaI in which X is hydrogen and Y is hydroxy and salts thereof.

The lactonization of the D-homopregnanes of formula VI or a salt thereofaccording to embodiment (e) of the present process can be carried out byknown methods. For example, by using a strong acid, such as hydrochloricacid, sulfuric acid or p-toluenesulfonic acid in a solvent, e.g., water,an alcohol, such as methanol, or mixtures thereof at a temperaturebetween about -50° C. and 100° C., preferably at room temperature.

The oxidation of the D-homopregnanes of formula VII according toembodiment (f) of the present process can be carried out according tothe Oppenauer procedure, e.g., with aluminum isopropylate, withoxidizing agents, such as chromium trioxide, e.g., Jones' reagent,according to the Pfitzner-Moffatt procedure with dimethylsulfoxide/dicyclohexylcarbodiimide (the initially obtained Δ⁵ -3-ketonerequiring subsequent isomerization to the Δ⁴ -3-ketone) or withpyridine/sulfur trioxide. When oxidizing agents such as bromine/lithiumbromide/lithium carbonate in dimethylformamide are used or when theoxidation is performed according to the Oppenauer procedure in thepresence of benzoquinone, the product obtained contains a 3-keto-Δ⁴,6-function. In order to obtain a 3-keto-Δ¹,4,6 -compound of formula I,the oxidation is suitably carried out using, e.g.,2,3-dichloro-5,6-dicyanobenzoquinone.

The starting materials of formulas II-VII hereinbefore, insofar as theirpreparation is not already known or described hereinafter, can beprepared by analogy to known methods or to methods describedhereinafter.

The D-homopregnanes provided by the present invention exhibitpharmacological activity. The D-homopregnanes show, among otheractivities, diuretic activity and are suitable for blocking the actionof aldosterone or desoxycorticosterone acetate. Accordingly, they can beused, for example, as potassium-sparing diuretics or for the flushing ofedemas. The D-homopregnanes may be administered, for example, in adosage of from about 0.1 mg/kg to 10 mg/kg per day.

The activity of the D-homopregnanes provided by the present inventioncan be determined as follows:

The compound to be tested is administered perorally in a gelatin capsuleto episiotamized and catheterized dogs. Immediately thereafter the dogsare injected subcutaneously with 0.5 μg/kg of aldosterone. The urine ofthe dogs is collected over a period of 6 hours. Thesodium(Na⁺)/potassium(K⁺) ratio calculated from the total excretion istaken as the measure of aldosterone antagonism. When the foregoingexperiment was carried out using7α-acetylthio-6α-methyl-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone(compound A) and7α-acetylthio-6α-methyl-3-oxo-D-homo-17aα-pregna-1,4,16-triene-21,17a-carbolactone(compound B) the results given in the following Table were obtained:

                  TABLE                                                           ______________________________________                                        Compound Dosage mg/kg                                                                              Na.sup.+ /K.sup.+ in % of the control                    ______________________________________                                        Control  0           100                                                      A        4           210                                                      B        1           244                                                      B        3           510                                                      B        10          652                                                      ______________________________________                                    

The D-homopregnanes provided by the present invention can be used asmedicaments: For example, in the form of pharmaceutical preparationswhich contain them in association with a compatible pharmaceuticalcarrier material. The carrier material can be an organic or inorganicinert carrier material suitable for enteral or parenteraladministration, such as, for example, water, gelatin, gum arabic,lactose, starch, magnesium stearate, talc, vegetable oils,polyalkyleneglycols, petroleum jelly, etc. The pharmaceuticalpreparations can be made up in a solid form, e.g., as tablets, dragees,suppositories or capsules, or in a liquid form, e.g., as solutions,suspensions or emulsions. The pharmaceutical preparations may besterilized and/or may contain adjuvants such as preserving, stabilizing,wetting or emulsifying agents, salts for varying the osmotic pressure orbuffers. They can also contain other therapeutically valuablesubstances.

The pharmaceutical preparations can be prepared by known methods bymixing a D-homopregnane of the present invention with conventionalnon-toxic, inert, solid and/or liquid carrier materials suitable fortherapeutic administration, e.g., the carrier materials previouslynamed, and, if desired, bringing the mixture into the desired dosageform.

The following Examples illustrate the present invention.

EXAMPLE 1

A mixture of 1.0 g of6-methylene-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone, 0.5g of sodium acetate, 50 mg of 5% palladium/carbon and 35 ml of ethanolwas heated under reflux for 15 hours. Simultaneously, 2 ml of 0.5%solution of cyclohexene in ethanol were added dropwise per hour. Thecatalyst was filtered and the filtrate was evaporated in vacuo. Theresidue was chromatographed on 55 g of silica gel. Elution withmethylene chloride/acetone (98:2) yielded 820 mg of pure6-methyl-3-oxo-D-homo-17aα-pregna-4,6,16-triene-21,17a-carbolactone,melting point 197°-198° C. (from acetone/hexane); [α]_(D) ²⁵ =+41°(c=0.1 in dioxan); ε₂₈₇ =22100.

The above lactone can also be obtained by acidifying a solution ofpotassium17a-hydroxy-6-methyl-3-oxo-D-homo-17aα-pregna-4,6,16-triene-21-carboxylatewith dilute hydrochloric acid.

6-Methylene-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone,used in this Example was prepared as follows:

3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone was convertedusing pyrrolidine in methanol into the enamine,3-(1-pyrrolidinyl)-D-homo-17aα-pregna-3,5,16-triene-21,17a-carbolactone.The enamine was treated with formaldehyde in benzene/methanol/water togive6β-hydroxymethyl-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone,melting point 246°-249° C.; [α]_(D) ²⁵ =+6° (c=0.1 in dioxan). Treatmentof the lactone with aqueous hydrochloric acid in dioxan yielded6-methylene-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone,melting point 216°-220° C.; [α]_(D) ²⁵ =+175° (c=0.1 in dioxan).

EXAMPLE 2

A solution of 1.0 g of6-methyl-3-oxo-D-homo-17aα-pregna-4,6,16-triene-21,17a-carbolactone in10 ml of thioacetic acid was heated at reflux for 6 hours. The excessthioacetic acid was evaporated in vacuo and the residue waschromatographed on 100 g of silica gel. Elution with hexane/acetoneyielded 0.9 g of pure7α-acetylthio-6α-methyl-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone,melting point 215°-217° C. (from acetone/hexane); [α]_(D) ²⁵ =-16°(c=0.1 in dioxan); ε₂₃₇ =19900.

EXAMPLE 3

A solution of 1.0 g of7α-acetylthio-6α-methyl-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactoneand 0.9 g of 2,3-dichloro-5,6-dicyanobenzoquinone in 50 ml of dioxan wasboiled under reflux for 48 hours. The cooled solution was filteredthrough 20 g of Alox (activity II) and the product was eluted completelywith 300 ml of ethyl acetate. The eluate yielded, after evaporation ofthe solvent, 1.0 g of crude product which was chromatographed on 50 g ofsilica gel. Elution with hexane/acetone (6:1) yielded 730 mg of pure7α-acetylthio-6α-methyl-3-oxo-D-homo-17aα-pregna-1,4,16-triene-21,17a-carbolactone,melting point 160°-162° C.; [α]_(D) ²⁵ =-29° (c=1.0 in dioxan); ε₂₄₀=17400.

EXAMPLE 4

A solution of 126 mg of potassium hydroxide (85%) in 0.68 ml of waterwas added to a solution of 700 mg of6-methyl-3-oxo-D-homo-17aα-pregna-4,6,16-triene-21,17a-carbolactone in 7ml of 2-propanol and the mixture was heated to reflux for 30 minutes.The solution was evaporated to dryness in vacuo and the residue wasfreed from water by addition and evaporation of absolute ethanol. Theresidue was suspended in 30 ml of ethyl acetate and the product wasfiltered off under suction. After drying overnight in vacuo at 60° C.,there was obtained 800 mg of pure potassium17a-hydroxy-6-methyl-3-oxo-D-homo-17aα-pregna-4,6,16-triene-21-carboxylate;[α]_(D) ²⁵ =-120° (c=0.1 in methanol); ε₂₉₀ =22800.

EXAMPLE 5

A mixture of 1.0 g of6-methylene-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone, 200mg of 5% palladium-on-carbon, 5 ml of benzene and 5 ml of cyclohexenewas heated at reflux under argon for 12 hours. The cooled mixture wasfiltered and the filtrate was evaporated in vacuo. Recrystallization ofthe crude product from ethanol and acetone gave pure6β-methyl-3-oxo-D-homo-17aα-pregna-4,16-diene-21,17a-carbolactone,melting point 238°-240° C.; [α]_(D) ²⁵ =+2° (c=0.1 in dioxan); ε₂₄₁=15700.

EXAMPLE 6

2.5 g of3β-hydroxy-6-methyl-D-homo-17aα-pregna-5,16-diene-21,17a-carbolactonewas dissolved in 67 ml of dimethylformamide. Lithium bromide (3.1 g) andlithium carbonate (3.1 g) were added to the mixture. With stirring andgassing with argon the white suspension was warmed to 80° C. At thistemperature, was added dropwise within 80 minutes a solution of 2.62 gof bromine in 21 ml of dioxan. After completion of the addition, theyellow-orange suspension was stirred at 80° C. for an additional 30minutes. The solution obtained was treated with 6 ml of glacial aceticacid, poured into 1000 ml of water and extracted with three 400ml-portions of ether/methylene chloride (4:1). The organic phases arewashed to neutrality with saturated sodium chloride solution, dried overmagnesium sulphate and evaporated to dryness. The crude product waspurified by chromatography on a 100-fold amount of silica gel withmethylene chloride/acetone (98:2). The fractions containing the producewere pooled and recrystallized from acetone/hexane to give3-oxo-6-methyl-D-homo-1;7aαpregna-4,6,16-triene-21,17a-carbolactone ascolorless crystals, melting point 197°-198° C.; [α]_(D) ²⁵ =+41° (c=0.1in dioxan).

The starting material can be prepared as follows:

Dimethylsulphoxonium methylide was treated with3β-hydroxy-6-methylandrost-5-en-17-one in dimethyl sulphoxide to give17,20-epoxy-3β-hydroxy-6-methyl-21-norpregn-5-ene. The epoxide wascleaved with ammonia under pressure to give20-amino-3β,17-dihydroxy-6-methyl-21-norpregn-5-ene. The latter wassubjected to Demjanov ring-expansion to give3β-hydroxy-6-methyl-D-homoandrost-5-en-17a-one which, by brominationwith cupric bromide in boiling methanol and susequent cleavage ofhydrogen bromide using calcium carbonate in boiling dimethylacetamide,was converted via17a-bromo-3β-hydroxy-6-methyl-D-homoandrost-5-en-17a-one into3β-hydroxy-6-methyl-D-homoandrosta-5,16-dien-17a-one. Reaction with thelithium Grignard 3-bromo-propionaldehyde dimethylacetal and subsequentacetylation with acetic anhydride/pyridine yields3β-acetoxy-21-dimethylacetal-17a-hydroxy-6-methyl-D-homo-17aα-pregna-5,16-diene.The acetal was cleaved with an aqueous 70% acetic acid solution to givethe corresponding aldehyde. The aldehyde cyclized spontaneously to give3β-acetoxy-6-methyl-D-homo-17aα-pregna-5,16-diene-21,17a-carbolactol.Jones oxidation yields the corresponding 21,17a-carbolactone which issaponified with potassium carbonate in methanol to give3β-hydroxy-6-methyl-D-homo-17aα-pregna-5,16-diene-21,17a-carbolactone.

The following Examples illustrate typical pharmaceutical preparationscontaining the D-homopregnanes provided by the present invention:

EXAMPLE A

A tablet for oral administration contains the following ingredients:

D-Homopregnane of formula I or salt thereof: 25 mg

Maize starch: 100 mg

Lactose: 50 mg

Polyvinylpyrrolidone: 15 mg

Magnesium stearate: 2 mg

EXAMPLE B

A capsule for oral administration contains the following ingredients:

D-Homopregnane of formula I or salt thereof: 25 mg

Maize starch: 125 mg

Lactose: 125 mg

We claim:
 1. A D-homopregnane of the formula ##STR9## wherein X ishydrogen and Y is hydroxy; R⁶ is hydrogen; R⁷ is lower alkanoylthio oraroylthio; and the dotted line in the 1,2-position of the A-ringtogether with the corresponding solid line denotes a single or doublecarbon to carbon bond, or a pharmaceutically-acceptable basic additionsalt thereof.